1. Field of the Invention
This invention concerns 2-(3-pyridylmethyl)naphthalene-6-carboxylic acid as an inhibitor of thromboxane synthetase activity and its use as an agent in the treatment of diseases characterized by an overproduction of thromboxane or an imbalance of thromboxane/prostacyclin.
2. Related Disclosures
Research work has established that in many tissues the major product of arachidonic acid metabolism by the cyclooxygenase enzyme system is either of two unstable substances, thromboxane A.sub.2 (TxA.sub.2) or prostacyclin (PGI.sub.2). The discovery of TxA.sub.2 and PGI.sub.2 has significantly increased our understanding of vascular homeostasis. PGI.sub.2 for instance is a powerful vasodilator and inhibitor of platelet aggregation, and in this last respect is the most potent endogenous substance so far discovered. The PGI.sub.2 synthetase enzyme is located in the endothelial layer of the vasculature, and while it has its own cyclooxygenase system it can utilize endoperoxides released by blood platelets when thromboxane synthetase is inhibited.
TxA.sub.2 is synthesized by the thromboxane synthetase enzyme which is located in, for example, the blood platelets. TxA.sub.2 is a powerful vasoconstrictor and pro-aggregatory substance, the direct opposite functions to those of PGI.sub.2. A balance in favor of PGI.sub.2 is regarded as beneficial in many conditions such as thrombosis, atherosclerosis, vasospastic cardiovascular disease, diabetes, renal disorders, inflammation, endotoxic shock and possibly even tumor metastasis.
The foregoing demonstrates the desirability of altering the prostacyclin/thromboxane ratio in favor of the former. One method of attempting to achieve this goal is to take advantage of the fact that the immediate precursor to both PGI.sub.2 and TxA.sub.2 is the same substance, the unstable endoperoxide PGH.sub.2. If the synthesis of TxA.sub.2 can be blocked, it is then reasonable to expect that more PGH.sub.2 will be available for conversion to PGI.sub.2. This activity has been demonstrated by several compounds, e.g., dazoxiben, but the levels of prostacyclin thus produced are quite low and may not be therapeutically useful.
Certain 2-(3-pyridylmethyl)naphthalene-6-carboxylic acids and 2-(3-pyridylmethyl)naphthalene-7-carboxylic acids are broadly disclosed in U.S. Pat. No. 4,590,200 to Cross et al. as thromboxane synthetase inhibitors. Of the large family of compounds disclosed, 2-(3-pyridylmethyl)-naphthalene-7-carboxylic acids are indicated as preferred compounds. In particular, 1-methyl-2-(3-pyridylmethyl)-naphthalene-7-carboxylic acid is shown as one of nine most preferred compounds. Surprisingly, we have now discovered that 2-(3-pyridylmethyl)-naphthalene-6-carboxylic acid has unexpectedly greater activity as a thromboxane synthetase inhibitor than 2-(3-pyridylmethyl)-naphthalene-7-carboxylic acid by a factor of about 200.